Funds are requested for purchase of a state-of-the-art 300 keV liquid helium Transmission Electron Cryo-Microscope with a Field Emission Gun. To leverage the funds provided by this NIH program, approximately 40% of the funds for this microscope will be derived from institutional sources at the University of Virginia. Two of the PIs use electron cryo-microscopy (cryo-EM) as their primary tool and will be the main users of this microscope. In addition, the acquisition of this instrument will be crucial for recruiting a third electron microscopist to the University of Virginia. There exists a significant community of NIH-funded investigators currently at the University of Virginia who will benefit greatly from the presence of this microscope. The need for this instrument arises from recent progress on a number of projects which show that existing microscopes at the University of Virginia limit continued progress. These projects include helical filaments, icosahedral viruses and two-dimensional crystals. Recent breakthroughs have been made in several areas, such as reconstructions of bacterial pili filamentous phage and HIV-1 capsids, and several indications suggest that much greater progress may be possible with a state-of-the-art microscope. The proposed microscope has an envelope function that decays much more slowly than the microscopes currently available, and this will allow us to obtain higher resolution structures. PUBLIC HEALTH RELEVANCE: We will use a higher resolution electron microscope to advance projects currently funded by the NIH. The higher resolution structures that we will obtain from this microscope will have an impact on matters of public health ranging from bacterial pathogenesis to heart disease to cancer to AIDS.